Method of treating binge eating disorder

ABSTRACT

The invention provides methods of treating binge eating disorders, obesity resulting from binge eating behavior, and depression. The invention includes methods of treating certain co-morbidities in ADHD and ADD patients; for example the invention includes methods of treating generalized anxiety disorder, obsessional and ruminative thought disorders, and obsessive/compulsive behavior in ADHD and ADD patients. The invention also includes combination methods of treatment in which an amphetamine prodrug, methylphenidate prodrug, or methylphenidate analog is administered with one or more other active agents. Packaged pharmaceutical compositions containing an amphetamine or methylphenidate prodrug, instructions for using the pro drug to treat certain disorders, and optionally one or more other active agents are provided by the invention.

FIELD OF INVENTION

The inventor has discovered that amphetamine prodrugs andmethylphenidate prodrugs are useful for treating a number of centralnervous system disorders. Methods of treating binge eating disorders,obesity resulting from binge eating behavior, and depression areincluded herein. The invention includes methods of treating certainco-morbidities in ADHD (Attention-Deficit Hyperactivity Disorder) andADD patients; for example the invention includes methods of treatinggeneralized anxiety disorder, obsessional and ruminative thoughtdisorders, and obsessive/compulsive behavior in ADHD and ADD patients.Methods of treatment include methods in which the amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog is the only activeagent. The invention also includes combination methods of treatment inwhich an amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog is administered with one or more other activeagents. Methods of use described herein include informing a user that anamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogmay be used to treat any of the disorders listed above. The inventionincludes pharmaceutical compositions comprising an amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog together with one ormore other active agents in a single dosage form. Packagedpharmaceutical compositions containing an amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog with instructions forusing the composition to treat one of the disorders listed above arealso provided.

BACKGROUND Binge Eating Disorder and Obesity Resulting from Binge EatingDisorder

Binge Eating Disorder is a form of Eating Disorder Not OtherwiseSpecified according the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV-TR). As defined by the DSM-IV-TR, it is characterizedby recurrent binge eating episodes.

Commonly described symptoms of binge eating disorder include frequentdieting and weight loss, hoarding of food, hiding empty food containers,eating late at night, attribution of one's successes and failures toweight, avoiding social situations where food may be present, andfeeling depressed or anxious. Binge eating also may cause rapid andunhealthy weight gain (or loss), weight fluctuations, and chronicerratic eating behavior. Binge eating disorder and symptoms associatedwith binge eating disorder may result in obesity though obesity is notnecessarily a result of binge eating disorder. Further, patients withbinge eating disorder are often not obese and may even have a belownormal weight.

The biological basis of binge eating disorder is poorly understood.Binge eating disorder is difficult to treat and carries significantmedical and psychiatric risks. Pharmacologic interventions have been oflimited success and sometimes cause a worsening of binge eatingsymptoms. A number of psychotropic medications, including but notlimited to antidepressants, antipsychotics, antimanic agents, and moodmodulating medications are known to cause binge eating, dysregulation ofappetite, and weight gain. Binge eating behaviors and weight gain may bea direct effect of such medication(s). Psychotropic medications may alsoexacerbate an underlying binge eating disorder in some patients.

Medical complications associated with binge eating disorder include highblood pressure, high cholesterol and triglycerides, kidney disease (andfailure), gallbladder disease, arthritis, bone deterioration, stroke,upper respiratory infections, skin disorders, menstrual irregularities,ovarian abnormalities, and pregnancy complications. Psychiatric problemsassociated with, or exacerbated by, binge eating disorder includedepressive disorders, mood disorders, anxiety disorders, ADHD and ADD,personality disorders, other eating disorders, suicidal thoughts, andsubstance abuse disorders.

Individuals with binge eating disorder may respond to treatment withantidepressants, though such medications may contribute to a worseningof binge eating symptoms, along with weight gain, either at the outsetof treatment or over time.

Depression

Depression is often difficult to treat, as some patients fail to respondto an initial pharmacologic intervention and a decision must be made toswitch agents, augment with another medication(s), or combine multiplepharmacologic agents. Combining medications, while often helpful, cansometimes be problematic with added side effect burdens. Side effects ofcertain psychotropic medication sometimes used to offer adjuncttreatment to patients already taking antidepressants may include weightgain and obesity.

Individuals treated for major depressive disorders may show a positiveresponse or full remission of symptoms to medication treatment, thoughrecent clinical evidence suggests remission rates following an adequatecourse of monotherapy treatment may as low as 30-40%. Further, clinicalstudies suggest an unusually large percentage of depressed individualstreated with antidepressant medication, greater than 30-40% in variousclinical studies, show only a partial response (for example, fullremission is not achieved but there is some measure of improvement indepressive symptoms). Some patients may be ‘refractory’ or ‘resistant’to treatment and fail to respond to one, or in some cases, multiplemonotherapy and combination antidepressant medication treatments.

Major depressive disorders similarly may lead to deteriorating physicalhealth and may increase the risk of morbidity and mortality in patientswith concurrent medical conditions.

Similarly, depressive disorders are often associated with, or mayexacerbate, other mood disorders, anxiety disorders, attention deficithyperactivity disorder (ADHD or ADD), psychotic disorders, personalitydisorders, eating disorders, cognition and cognitive disorders,substance abuse disorders, and suicidal ideation.

There exists an unmet and important clinical need for treatments forbinge eating disorders, obesity resulting from binge eating behavior,and depression that is only partially responsive to medication andintractable (e.g. ‘treatment-resistant’) depression. The presentinvention fulfills this need and provides additional advantagesdescribed herein.

SUMMARY OF THE INVENTION

The inventor has discovered that amphetamine prodrugs, includinglisdexamfetamine dimesylate, methylphenidate prodrugs, and certainmethylphenidate analogs, are useful for treating binge eating disorders,obesity resulting from binge eating behavior, and depression.Furthermore amphetamine prodrugs, methylphenidate prodrugs, and certainmethylphenidate analogs have been found useful for treating certainco-morbidities in ADHD and ADD patients. The invention includes methodsof treating generalized anxiety disorder, obsessional and ruminativethought disorders, and obsessive/compulsive behavior in patients,particularly in ADHD/ADD patients. Methods of using amphetamineprodrugs, methylphenidate prodrugs, or methylphenidate analogs, as amonotherapy for treating these conditions and disorders or incombination with one or more other active agents are provided herein.

The invention includes a method of treating binge eating disorder orobesity resulting from binge eating behavior, comprising diagnosing apatient as having a binge eating disorder or obesity resulting frombinge eating behavior and providing an effective amount of amphetamineprodrug, methylphenidate prodrug, or methylphenidate analog to thepatient.

The invention also includes a method of treating depression comprisingdiagnosing a patient as having depression and providing an effectiveamount of amphetamine prodrug, methylphenidate prodrug, methylphenidateanalog to the patient.

The invention further provides a method of treating generalized anxietydisorder, obsessional and ruminative thought disorders, orobsessive/compulsive behavior in a patient having ADHD or ADD or otherpatient. In an AMID or ADD patient this method comprises diagnosing apatient having ADHD or ADD and as also having at least one ofgeneralized anxiety disorder, obsessional and ruminative thoughtdisorders, or obsessive/compulsive behavior, and providing an effectiveamount of amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog to the patient.

In each of these methods the amphetamine prodrug, methylphenidateprodrug, or methylphenidate analog may be provided as the only activeagent, i.e. as a monotherapy, or may be provided together with one ormore other active agents, i.e. as a combination, adjunct, oraugmentation therapy.

In a separate embodiment, the invention includes a method of using anamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogcomprising informing a user that the amphetamine prodrug,methylphenidate prodrug, methylphenidate analog may be used to treatbinge eating disorder or obesity resulting from binge eating behavior.The invention also includes a method of using an amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog comprising informinga user that the amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog may be used to treat depression. The inventionfurther includes a method of using an amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog comprising informinga user that the amphetamine prodrug, methylphenidate prodrug,methylphenidate analog may be used to treat certain co-morbidities inADHD and ADD patients, or may be used to treat certain CNS disorders inpatients not diagnosed with ADHD or ADD, including generalized anxietydisorder, obsessional and ruminative thought disorders, andobsessive/compulsive behavior. The invention includes (i)lisdexamfetamine dimesylate and (ii) one or more other active agent(s)combined in a single dosage form.

The invention includes articles of manufacture comprising an amphetamineprodrug, methylphenidate prodrug, or methylphenidate analog in acontainer and printed labeling. The printed labeling states that theamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogis useful for treating a binge eating disorder, obesity resulting frombinge eating behavior, or depression. In other embodiments the printedlabeling states that the amphetamine prodrug, methylphenidate prodrug,methylphenidate analog is useful for treating generalized anxietydisorder, obsessional and ruminative thought disorders, andobsessive/compulsive behavior in a patient, particularly in a patienthaving ADHD or ADD.

DETAILED DESCRIPTION Terminology

Prior to setting forth the invention in detail, it may be helpful toprovide definitions of certain terms to be used herein. Compounds of thepresent invention are described using standard nomenclature. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as is commonly understood by one of skill in the art towhich this invention belongs.

The terms “a” and “an” do not denote a limitation of quantity, butrather denote the presence of at least one of the referenced item.

An “active agent” means any compound, element, or mixture that whenadministered to a patient alone or in combination with another agentconfers, directly or indirectly, a physiological effect on the patient.When the active agent is a compound, salts, solvates (includinghydrates) of the free compound or salt, crystalline and non-crystallineforms, as well as various polymorphs of the compound are included.Compounds may contain one or more asymmetric elements such asstereogenic centers, stereogenic axes and the like, e.g. asymmetriccarbon atoms, so that the compounds can exist in differentstereoisomeric forms. These compounds can be, for example, racemates oroptically active forms. For compounds with two or more asymmetricelements, these compounds can additionally be mixtures of diastereomers.For compounds having asymmetric centers, it should be understood thatall of the optical isomers in pure form and mixtures thereof areencompassed. In addition, compounds with carbon-carbon double bonds mayoccur in Z- and E-forms, with all isomeric forms of the compounds beingincluded in the present invention. In these situations, the singleenantiomers, i.e., optically active forms can be obtained by asymmetricsynthesis, synthesis from optically pure precursors, or by resolution ofthe racemates. Resolution of the racemates can also be accomplished, forexample, by conventional methods such as crystallization in the presenceof a resolving agent, or chromatography, using, for example a chiralHPLC column. A “dosage form” means any unit of administration of anactive agent.

“Binge eating disorder” is a form of Eating Disorder Not OtherwiseSpecified. As defined by the DSM-IV-TR, it is characterized by recurrentbinge eating episodes. Such episodes include eating larger amounts offood than normal during a short period of time (for instance, within atwo hour period) and a lack of control over eating during the bingeepisode (for instance, one cannot stop eating). According to theDSM-IV-TR, binge eating disorders are associated with three or more ofthe following symptoms: eating until uncomfortably full; eating largeamounts of food when not physically hungry; eating much more rapidlythan normal; eating alone on account of embarrassment over how much oneis eating; and feeling disgusted, depressed or guilty after overeating.Additionally, individuals with binge eating disorder feel distress abouttheir binging behavior. The DSM-IV-TR also characterizes binge eating tooccur, on average, at least 2 days a week for six months, while notbeing associated with the regular use of inappropriate compensatorybehaviors such as purging or excessive exercise and not occurringexclusively during the course of bulimia nervosa or anorexia nervosa. Asused herein “depression” includes major depressive disorder, dysthymicdisorder, depressive disorder not otherwise specified (for instance,premenstrual dysphoric disorder), and depressive episodes that may bepresent in another disorder (e.g. as in other mood disorders such asbipolar disorder or a mood disorder due to a general medical condition).

Depressive disorders represent one of four classes of mood disorderslisted in the DSM-IV-TR; the other major forms of mood disorders includebipolar disorders, mood disorders due to a general medical condition,and substance-induced mood disorders, all of which may demonstratesymptoms of depression or low mood. Major depressive episodes may bepresent in a depressive disorder, which according to the DSM-IV-TRinclude major depressive disorder, dysthymic disorder, and depressivedisorder not otherwise specified (for instance, premenstrual dysphoricdisorder).

Depressive symptoms or features such as low mood, diminished interest inactivities, psychomotor slowing or agitation, changes in appetite, poorconcentration or indecisiveness, excessive guilt or feelings ofworthlessness, and suicidal ideations may occur in the context ofdepressive disorders, bipolar disorders, mood disorders due to a generalmedical condition, substance-induced mood disorders, other unspecifiedmood disorders, and also may be present in association with a range ofother psychiatric disorders, including but not limited to psychoticdisorders, cognitive disorders, eating disorders, anxiety disorders andpersonality disorders. The longitudinal course of the disorder, thehistory and type of symptoms, and etiologic factors help distinguish thevarious forms of mood disorders from each other.

A “major depressive episode, according to the DSM-IV-TR, involves fiveor more of the following symptoms in the same 2 week period, signifyinga change from previous functioning, of which one symptom is either 1)depressed mood or 2) a loss of interest or pleasure. The other symptomsinclude weight loss or weight gain, insomnia or hypersomnia, psychomotorretardation or agitation, fatigue or lethargy, feelings of worthlessnessor excessive guilt, poor concentration, or recurrent thoughts of deathor suicide. Such symptoms cause significant distress or impairment andare not due to a general medical or substance abuse condition.

“Depression symptoms rating scale” refers to any one of a number ofstandardized questionnaires, clinical instruments, or symptominventories utilized to measure symptoms and symptom severity indepression. Such rating scales are often used in clinical studies todefine treatment outcomes, based on changes from the study's entrypoint(s) to endpoint(s). Such depression symptoms rating scales include,but are not limited to, The Quick Inventory of Depressive-SymptomatologySelf-Report (QIDS-SR₁₆), the 17-Item Hamilton Rating Scale of Depression(HRSD₁₇), the 30-Item Inventory of Depressive Symptomatology (IDS-C₃₀),or The Montgomery-Asperg Depression Rating Scale (MADRS). Such ratingsscales may involve patient self-report or be clinician rated. A 50% orgreater reduction in a depression ratings scale score over the course ofa clinical trial (starting point to endpoint) is typically considered afavorable response for most depression symptoms rating scales.“Remission” in clinical studies of depression often refers to achievingat, or below, a particular numerical rating score on a depressionsymptoms rating scale (for instance, less than or equal to 7 on theHRSD₁₇; or less than or equal to 5 on the QIDS-SR₁₆; or less than orequal to 10 on the MADRS).

Binge eating behavior may be assessed by different methods though iscommonly determined by the frequency of binge eating episodes occurringover a specific period of time (i.e., the number of binges per week; orthe mean number of binges over two week periods). Another form ofassessment may quantify the number of “binge-days”, that is, the numberof days in which the patient has binged in any form (i.e., whether onceor multiple times) and determining the frequency of binge-days over aspecific time frame.

“Generalized Anxiety Disorder” as defined by the DSM_IV-TR, and as theterm is used herein, is a disorder meeting the following criteria: A. Atleast 6 months of “excessive anxiety and worry” about a variety ofevents and situations. Generally, “excessive” can be interpreted as morethan would be expected for a particular situation or event. Most peoplebecome anxious over certain things, but the intensity of the anxietytypically manifests in the following manner:

A. There is significant difficulty in controlling the anxiety and worry.

B. The presence for most days over the previous six months of 3 or more(only 1 for children) of the following symptoms: 1. Feeling wound-up,tense, or restless, 2. Easily becoming fatigued or worn-out 3.Concentration problems, 4. Irritability, 5. Significant tension inmuscles, and 6. Difficulty with sleep.

C. The symptoms are not part of another mental disorder.

D. The symptoms cause “clinically significant distress” or problemsfunctioning in daily life. “Clinically significant” is the part thatrelies on the perspective of the treatment provider. Some people canhave many of the aforementioned symptoms and cope with them well enoughto maintain a high level of functioning.

E. The condition is not due to a substance or medical issue. Theseverity of Generalized Anxiety Disorder may be assessed using acommonly accepted test for assessing the anxiety severity, such as theHamilton Anxiety Rating Scale (HAM-A) or the Generalized AnxietyDisorder Severity Scale (GADSS).

“Obsessive behavior” may arise in many different clinical forms,including recurrent thoughts, impulses or images; perseverative thinkingpatterns; or highly ruminative mental behavior. Such symptoms often, butnot necessarily, occur in the context of obsessive-compulsive disorder.“Compulsive behavior,” sometimes referred to as ‘compulsions’, maysimilarly take a myriad of clinical forms, from more conventionalobsessive-compulsive disorder symptoms (i.e., “checking”, “ordering” or“hoarding” behaviors) to such symptoms as compulsive gambling andsubstance abuse, sexual and internet compulsions, and compulsiveexercising or lying. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS)is often used to assess symptom severity for patients that have bothobsessions and compulsions, with scores reflecting symptoms severity(for instance, 0-7 as ‘sub-clinical’ through 32-40 as ‘severe’).

“Obesity” is defined as a BMI (Body Mass Index)>30 (kg/m²).

“Efficacy” means the ability of an active agent administered to apatient to produce a therapeutic benefit in the patient.

The terms “amphetamine prodrug” and “methylphenidate prodrug” refer toany product that contains either an amphetamine (CAS Reg. No. 300-62-9)or methylphenidate (CAS Reg. No. 113-45-1) compound conjugated to achemical moiety such that the conjugated amphetamine or methylphenidatemust undergo a conversion in a patient's body to become the activeamphetamine or methylphenidate form. “Amphetamine” includes dextro andlevo amphetamine forms and all pharmaceutically acceptable amphetaminesalts. Conversion typically involves metabolism. “Methylphenidate” alsoincludes all methylphenidate optical isomers and all pharmaceuticallyacceptably methylphenidate salts. For example “methylphenidate” includespure dexmethylphenidate (α-phenyl-2-piperidineacetatehydrochloride,(R,R′)-(+)-) and racemic mixtures of d- and l-methylphenidate forms.

Lisdexamfetamine dimesylate, CAS Reg. No. 608137-32-3,(2S)-2,6-diamino-N-[(1S)-1-methyl-2-phenylethyl] hexanamidedimethanesulfonate, is an amphetamine prodrug in which L-lysine iscovalently bound to d-amphetamine. Lisdexamfetamine dimesylate is soldunder the trade name VYVANSE (Shire). It has the chemical formula:

“Lisdexamfetamine” is typically administered as a dimesylate salt butincludes all pharmaceutically acceptable salts of lisdexamfetamine freebase. The term “lisdexamfetamine” also encompasses all polymorphs andhydrates of this drug.

“Informing” in any of the above embodiments of the invention may occurby reference to, or providing, information material. Informing can alsooccur by presentation at a seminar, conference, or other educationalpresentation; or by providing an active agent with informationalmaterial to a user; or in a conversation between a pharmaceutical salesrepresentative and a medical care worker or between a medical careworker and a patient.

“Informational material” means any media providing information. Mediaincludes printed, audio, visual, or electronic media. Examples ofinformation material are flyer, an advertisement, a package insert for apharmaceutical product, printed labeling, an internet web site, aninternet web page, an internet pop-up window, or information recorded ona compact disk, DVD, an audio recording, or any other recording orelectronic medium.

A “medical care worker” means any worker in the health care field whomay need information regarding an active agent, including information onsafety, efficacy, dosing, administration, or pharmacokinetics. Examplesof medical workers include physicians, pharmacists, physician'sassistants, nurses, caretakers, emergency medical workers, andveterinarians.

A “patient” means any human or non-human animal in need of medicaltreatment. Medical treatment can include treatment of an existingcondition, such as a disease or disorder, prophylactic or preventativetreatment, or diagnostic treatment. In some embodiments the patient is ahuman patient.

As used herein “a pharmaceutical supplier” means any person (other thana medical care worker), business, charitable organization, governmentalorganization, or other entity involved in the transfer of active agentbetween entities, for profit or not. Examples of pharmaceuticalsuppliers include pharmaceutical distributors, pharmacies (online orphysical), foreign businesses or individuals importing active agent intothe United States, the hospitals, HMOs and the Veterans Administration.

“Pharmaceutically acceptable salts” includes derivatives of thedisclosed compounds, wherein the parent compound is modified by makingnon-toxic acid or base addition salts thereof, and further refers topharmaceutically acceptable solvates, including hydrates, of suchcompounds and such salts. Examples of pharmaceutically acceptable saltsinclude, but are not limited to, mineral or organic acid addition saltsof basic residues such as amines; alkali or organic addition salts ofacidic residues such as carboxylic acids; and the like, and combinationscomprising one or more of the foregoing salts. The pharmaceuticallyacceptable salts include non-toxic salts and the quaternary ammoniumsalts of the parent compound formed, for example, from non-toxicinorganic or organic acids. For example, non-toxic acid salts includethose derived from inorganic acids such as hydrochloric, hydrobromic,sulfuric, sulfamic, phosphoric, nitric and the like; other acceptableinorganic salts include metal salts such as sodium salt, potassium salt,cesium salt, and the like; and alkaline earth metal salts, such ascalcium salt, magnesium salt, and the like, and combinations comprisingone or more of the foregoing salts.

Pharmaceutically acceptable organic salts include salts prepared fromorganic acids such as acetic, trifluoroacetic, propionic, succinic,glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like; organic amine saltssuch as triethylamine salt, pyridine salt, picoline salt, ethanolaminesalt, triethanolamine salt, dicyclohexylamine salt,N,N′-dibenzylethylenediamine salt, and the like; and amino acid saltssuch as arginate, asparginate, glutamate, and the like, and combinationscomprising one or more of the foregoing salts.

“Providing” includes giving, selling, distributing, transferring (forprofit or not), manufacturing, compounding or dispensing.

A “product” or “pharmaceutical product” is a dosage form of an activeagent plus published material and optionally packing.

“Safety” means the incidence of adverse events associated withadministration of an active agent, including adverse effects associatedwith patient-related factors (e.g., age, gender, ethnicity, race, targetillness, abnormalities of renal or hepatic function, co-morbidillnesses, genetic characteristics such as metabolic status, orenvironment) and active agent-related factors (e.g., dose, plasma level,duration of exposure, or concomitant medication).

The term “therapeutically effective amount” or “effective amount” meansan amount effective, when administered to a human or non-human patient,to provide any therapeutic benefit. A therapeutic benefit may be anamelioration of symptoms, e.g., an amount effective to decrease thesymptoms of binge-eating disorder or a major depressive disorder. Incertain circumstances a patient may not present symptoms of a conditionfor which the patient is being treated. Thus a therapeutically effectiveamount of a compound is also an amount sufficient to provide asignificant positive effect on any indicia of a disease, disorder orcondition e.g. an amount sufficient to significantly reduce thefrequency and severity of binge eating behavior or depressive symptoms.A significant effect on an indicia of a disorder or condition includes astatistically significant in a standard parametric test of statisticalsignificance such as Student's T-test, where p<0.05; though the effectneed not be significant in some embodiments.

A “user” is a patient, a medical care worker, or a pharmaceuticalsupplier.

Amphetamine and Methylphenidate Prodrugs

Amphetamine has the chemical formula

Amphetamine prodrugs, and methods of preparing amphetamine prodrugs havebeen described previously. U.S. Pat. No. 7,105,486, which describes thepreparation of lisdexamfetamine, is hereby incorporated by reference atcols. 20 to 22 for its teachings regarding the synthesis of amino acidamphetamine prodrugs. In addition to amino acid prodrugs it is possibleto prepare a number of other amphetamine prodrugs by reacting theamphetamine amino group with a chemically labile moiety. It is withinthe ability of those of ordinary skill in the art of chemical synthesisto prepare carboxamide amphetamine prodrugs by reacting amphetamine withan aliphatic aldehyde and to prepare carbamate amphetamine prodrugs byreacting amphetamine with an aliphatic organic acid.

Methylphenidate has the chemical formula

The arrow indicates a chemically accessible site at which labile groupsmay be added to create methylphenidate prodrugs. Amino acidmethylphenidate prodrugs may be prepared via the general methodsdescribed in U.S. Pat. No. 7,105,486 for the preparation of amphetamineamino acid prodrugs. Amino acid methylphenidate prodrugs may comprisemethylphenidate covalently bound to a single amino acid at thepiperidine nitrogen or bound to a di- or tri-peptide at this position.It is also a matter of routine organic synthesis to prepare carboxamideand carbamate methylphenidate prodrugs by reacting methylphenidate withan aliphatic aldehyde or aliphatic organic acid.

Methylphenidate contains a secondary amine group and amphetaminecontains an amino group both of which may be reacted to form prodrugshaving a chemical moeity covalently attached to the amine or amino groupof the parent drug compound. Prodrugs of amine-containing compounds havebeen disclosed in U.S. Patent Application No. 2007/0123468, which ishereby incorporated by reference at paragraphs [0078]-[0137] for itsteaching regarding general classes of amine prodrugs, at paragraph[0140] for its teaching regarding amphetamine and methylphenidateprodrugs, at paragraphs [0176]-[0181] for its teachings ofmethylphenidate prodrug structures, and at paragraphs [0184]-[0189] forits teaching regarding prodrugs synthesis.

Methylphenidate Analogs

Methylphenidate analogs are compounds have a structure highly similar tomethylphenidate, and like methylphenidate bind to the brain dopaminetransporter and affect the reuptake of dopamine in the brain, but whichhave an extended duration of action relative to methylphenidate.Methylphenidate analogs include compounds having the general formula

where at least one of R₂ and R₄ is a non-hydrogen substituent differingfrom the group that occurs at the corresponding position inmethylphenidate and R₁ and R₅ are independently chosen from hydrogen,halogen, hydroxyl, C₁-C₂alkyl, and C₁-C₂alkoxy, and the like.Methylphenidate analogs have been disclosed in U.S. Non-provisionalPatent Application No. 2006/0100243, which is hereby incorporated byreference at paragraphs [0007]-[0021] for its teachings regarding themethylphenidate analog structures, at paragraphs [0055]-[0063] itsteachings regarding the methylphenidate analog structure and synthesis,and at paragraphs [0083]-[0085] for its exemplary synthesis ofmethylphenidate analogs.

Methods of Treatment

The invention provides methods of treating binge eating disorders,obesity resulting from binge eating behavior, and depression. Theinvention includes methods of treating certain co-morbidities in ADHDand ADD patients; the invention includes methods of treating generalizedanxiety disorder, obsessional and ruminative thought disorders, andobsessive/compulsive behavior in patients, particularly in ADHD and ADDpatients. The amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog may be the only active agent administered(monotherapy) or may be combined with one or more other active agents(combination, adjunct, or augmentation therapy).

The invention also provides methods of treating depression, weight gainand/or obesity associated with depression, and weight gain and/orobesity due to taking anti-depressant medications.

The invention provides a method of treating chronic fatigue syndrome,fatigue, amotivation, or cognitive deficits associated with fatiguecomprising diagnosing a patient as having chronic fatigue syndrome,fatigue, amotivation or cognitive deficits associated with fatigue andproviding an effective amount of amphetamine prodrug, methylphenidateprodrug, or methylphenidate analog to the patient.

In a first embodiment the invention includes a method of treating bingeeating disorder or obesity resulting from binge eating behavior,comprising diagnosing a patient as having a binge eating disorder orobesity resulting from binge eating behavior and providing an effectiveamount of amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog to the patient, wherein the amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog is provided as theonly active agent or is provided together with one or more additionalactive agents.

In another embodiment the invention provides a method of treatingdepression comprising (i) diagnosing a patient as having depression and(ii) providing an effective amount of amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog to the patient,wherein the amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog is provided as the only active agent or isprovided together with one or more additional active agents.

Psychosocial intervention may play an important role in treatment ofboth depression and binge eating disorder. Psychosocial interventionincludes cognitive-behavior therapy, dialectical-behavior therapy,interpersonal therapy, psychodynamic therapy and group therapy.

While amphetamine and methylphenidate based stimulant medications havebeen associated with the side effect of appetite suppression andenhanced mood, their release mechanisms are of short or intermediateduration. As plasma levels of these drugs drop, patients typicallyexperience symptoms associated with low drug levels. Even extendedrelease amphetamine or methylphenidate formulations leave individualswith a ‘wear off’ effect for a sufficient part of the day, in which themedication loses its effects including appetite suppressant properties.‘Wear off’ effects lead to problematic symptoms or side effects,sometimes of a ‘rebound’ nature, including the urge to have moremedication, feeling dysphoric or low, feeling hungry or eating more,binge eating, fatigue, amotivation, and poor concentration.

Lisdexamfetamine dimesylate, given its slower and gradual release,confers certain significant advantages not seen previously with otheramphetamine or methylphenidate stimulants. There is minimal ‘wear-off’effect, a smoother distribution of drug over time, and no apparent needfor dosing beyond once per day as significant effects have beendemonstrated for up to 12 hours after administration. The uniqueclinical profile of lisdexamfetamine dimesylate offers all the benefitsof a stimulant treatment for a full day, a much-needed advance requiredfor sustained clinical benefit in depressive and binge eating disorders.Such a profile is particularly significant for depressive disorders,where a low mood is characteristically present through the entire dayand often worse later in the day. Problems with concentration orfatigue, associated with depression or which may be associated withother conditions, may receive notably significant benefit as well.Additionally, treatment of binge eating behavior with lisdexamfetaminedimesylate, where symptoms may intensify toward the end of the day or inthe evening or may have some relation to feelings of dysphoria as otherstimulant medications ‘wear off’, would achieve surprisingly positivebenefit. Lisdexamfetamine dimesylate is thought to confer less‘euphorgenic’ properties, which may also mitigate feeling down as themedication “wears off.”

Lisdexamfetamine dimesylate, sold under the trade name VYVANSE (Shire),is FDA approved for the treatment of Attention-Deficit HyperactivityDisorder. Other psychostimulant treatments for Attention-DeficitHyperactivity Disorder include both amphetamine (e.g. ADDERALL andADDERALL XR) and methylphenidate (e.g. RITALIN and CONCERTA)preparations. Stimulant drugs, including lisdexamfetamine dimesylate,are believed to act via potentiation of dopamine and norepinephrineneurotransmission in the central nervous system.

Amphetamine prodrugs, including lisdexamfetamine, methylphenidateprodrugs, and certain methylphenidate analogs are unexpectedly effectivefor treating a number of disorders exacerbated by non-chemicallymodified immediate release and extended release amphetamine andmethylphenidate including binge eating disorder and depression. Incertain embodiments a patient is diagnosed as having a binge eatingdisorder or obesity related to binge eating behavior and an amount ofamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogis provided to the patient; wherein the amount is effective to reducethe number of binge eating episodes in a one month time period, toproduce a weight loss of 5% or greater of the patient's body mass withina six month treatment period, or significantly reduce the patient'striglyceride levels by 20% or more over a six month treatment period.

Methods of treatment include administering an effective amount of anamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogwherein the effective amount is an amount effective to decrease thenumber of binge eating episodes per month or decrease the number of daysin a month in which the patient experiences a binge eating episode.

In other embodiments the effective amount of amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog is an amounteffective to decrease depressive symptoms. Preferably the decrease indepressive symptoms is a 50% or greater reduction of symptoms identifiedon depression symptom rating scale or is constituted by a depressionsymptom rate scale score below a particular value that may signifyremission of a depressive episode (for instance, less than or equal to 7on the HRSD₁₇).

The invention provides methods of treating weight gain associated withdepression or caused by treatment with antidepressant medications.

Treatment approaches for major depressive disorder or other disorders inwhich depressive symptoms are present typically do not include themanagement of obesity. Similarly, treatment approaches for obesitytypically do not address depressive symptoms. Pharmacologic treatmentsfor mood disorders may actually contribute to weight gain, obesity, orincreased abdominal girth, with potentially untoward psychologicaleffects or medical sequelae such as hypertriglyceridemia, metabolicsyndrome, or type II diabetes. While the mood disorder or depressivesymptoms may be effectively treated with such pharmacologic agents,associated weight gain can carry a number of serious risks. Treatmentsthat address both depression and obesity, as either monotherapy or asadjunct treatment, are much needed clinically and would serve apopulation with unmet clinical needs. Further, as demonstrated by theputative link of binge eating to such conditions as depression andobesity, pharmacologic interventions that ameliorate binge eating mayhave particular added value.

The relationship between mood disorders and obesity has been examined ina number of clinical and demographic studies, though the relationship iscomplicated and poorly understood. Current paradigms that link the twoconditions suggest the possibility that shared genetic vulnerabilities,neurobiology (in particular the hypothalamic-pituitary-adrenocortical[HPAC] axis), or social factors may play important roles. Demographicstudies suggest obesity, including associated conditions of ‘overweight’and ‘abdominal obesity,’ are common to patients treated for mooddisorders and represent a risk factor for depression, in particular forfemales, children, and individuals with child-onset major depression. Itis well established that major depressive disorder commonly will presentwith ‘atypical’ features, as recognized in the DSM-IV-TR, with symptomsof weight gain, low energy, and inactivity. Binge eating symptoms mayalso accompany such forms of depression. Interestingly, obeseindividuals with binge eating disorder or behavior have been shown tohave higher rates of mood disorders. There is research to suggest thatwomen having major depressive disorder may be particularly disposed toweight gain and obesity and, as such, may represent either a distinctsubset of depression or of obesity, which may even be linked topolycystic ovarian syndrome. More recent data suggests an even moreconclusive link between obesity and atypical features of depression inwomen with bipolar disorder. In fact, the DSM-IV-TR recognizes that‘atypical’ features of depression are 2-3 times more common in womenthan in men.

The invention further includes methods of using lisdexamfetaminedimesylate, comprising informing a user that the lisdexamfetaminedimesylate may be used to treat binge eating disorders, obesityresulting from binge eating behavior, or depression. The inventionincludes methods of using lisdexamfetamine dimesylate comprisinginforming a user that the lisdexamfetamine dimesylate may be used totreat certain co-morbidities in ADHD and ADD patients, including methodsof treating generalized anxiety disorder, obsessional and ruminativethought disorders, and obsessive/compulsive behavior in ADHD and ADDpatients. The user may be informed of the usefulness of lisdexamfetaminedimesylate, or other amphetamine prodrug, a methylphenidate prodrug, ora methylphenidate analog for the treatment of the above-mentioneddisorders and conditions by reference to a package insert associatedwith the container. The informing may also be by reference toinformation material; by reference to a package active agent insert, aflyer or an advertisement; by presentation of information at a seminar,conference, or other educational presentation; or by a conversationbetween a pharmaceutical sales representative and a medical care worker.

Frequency of dosage may vary depending on the compound used and theparticular condition or disorder to be treated or prevented. For mostdisorders a dosage regimen of once per day is preferred. Dosage regimensin which the amphetamine prodrug or methylphenidate prodrug isadministered 2 times daily may occasionally be more helpful. In certainembodiments, 2.5 mg to 250 mg lisdexamfetamine dimesylate isadministered per day or 15 to 100 mg lisdexamfetamine dimesylate perday, or about 50 mg per day lisdexamfetamine dimesylate is administered.Lisdexamfetamine dimesylate is typically administered once daily in themorning, with preferred dosing in the range of 15-70 mg per day, thoughin some embodiments daily doses of less than 15 mg, for example fromabout 2.5 mg to about 15 mg, or from about 2.5 to about 12.5 mg areuseful for treating binge eating behaviors or depression.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease in the patient undergoing therapy. Patients maygenerally be monitored for therapeutic effectiveness using assayssuitable for the condition being treated or prevented, which will befamiliar to those of ordinary skill in the art.

Combination Methods

The invention provides a method of treating of central nervous systemdisorders in which an amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog is provided to a patient together with one ormore additional active agents. Such methods are referred to as“combination methods” of treatment. Combination methods of treatingbinge eating disorders, obesity resulting from binge eating behavior,and depression are included herein. The invention includes combinationmethods of treating certain co-morbidities in ADHD and ADD patients; forexample the invention includes combination methods of treatinggeneralized anxiety disorder, obsessional and ruminative thoughtdisorders, and obsessive/compulsive behavior in ADHD and ADD patients.

The additional active agent may be administered separately from theamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogor may be combined with the additional active agent.

The invention also includes combination methods of treatment in which anamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogis administered together with one or more forms of therapy, psychosocialsupport, or medical management. Such forms of psychosocial interventioninclude cognitive-behavior therapy, dialectical-behavior therapy,interpersonal therapy, psychodynamic therapy and group therapy.

The invention also includes combination methods of treatment in whichthe one or more other active agent(s) is an appetite suppressant, aweight loss drug, an anti-obesity agent, an anti-diabetes agent, anantidepressant, an anxiolytic, a selective serotonin reuptake inhibitor,a serotonin 5HT receptor partial agonist or antagonist, a norepinephrinedopamine reuptake inhibitor, a serotonin norepinephrine dopaminereuptake inhibitor, a serotonin 5-HT1a partial agonist, a serotonin5-HT1b agonist, a serotonin 5-HT2 antagonist, a serotonin 5-HT6antagonist, a serotonin-2 antagonist reuptake inhibitor, a serotonin-1agonist reuptake inhibitor, a mixed serotonin antagonist reuptakeinhibitor/partial agonist/dopamine agonist, an alpha-2antagonist/serotonin 5HT2-3 receptor antagonist, a serotonin modulatoror stimulator, a mixed serotonin antagonist/melatonin agonist, a mixedserotonin dopamine antagonist, a tricyclic antidepressant, a tetracyclicantidepressant, a bis-aryl-sulphanyl modulator, a beta-3 adrenoreceptorstimulator or agonist, a beta-3 adrenoreceptor antagonist, a nicotinicacetylcholine receptor agonist or antagonist, an enkephalinergicmodulator, an aprepitant, a neurokinin (NK) antagonist, a NK1, 2, or 3antagonist, a neuropeptide (NP) γ antagonist, a NPY1, 2, or 3, or 5antagonist, a substance P antagonist, a corticotrophin-releasing hormone(CRH or CRF) antagonist, a CRH(or CRF)-1 antagonist, a glucocorticoidreceptor agonist or partial agonist, a glucocorticoid receptorantagonist, a glucocorticoid receptor type II antagonist, ananti-convulsant, a GABA modulator, a GABA inverse agonist or partialagonist, a GABA receptor antagonist, a GABA channel antagonist, a GABAreuptake inhibitor, a glutamate modulator, an mGluR receptor modulator,agonist or antagonist, an mGluR2/3 agonist, an mGluR5 antagonist, anestrogen receptor agonist or antagonist, a melatonin receptor agonist orantagonist, a glycine transporter inhibitor, an alpha-1 receptoragonist, an alpha-1 receptor antagonist, an alpha-2 receptor agonist, analpha-2 receptor antagonist, a vasopressin-1B (V1B) agonist orantagonist, an NMDA receptor modulator (i.e., a partial agonist,agonist, or antagonist), an ampakine modulating agent, an opioidantagonist, an opioid partial agonist, a benzodiazepine, ananti-psychotic, a dopamine receptor agonist or analog, a wakefulnesspromoting agent, an anti-manic agent, a mood modulating (i.e.,stabilizing) agent, a cholinesterase inhibitor, an anti-amyloid agent,an anti-aggregant, a beta-secretase inhibitor, a beta-amyloidantagonist, a monoamine oxidase inhibitor, an anti-migraine agent, amelanocyte inhibiting factor, or a combination of the foregoing.

Weight-loss drugs include, but are not limited to, lipase inhibitors.Non-limiting examples of weight loss drugs include orlistat.

Anti-diabetes drugs include, but are not limited to, hypoglycemicagents. Non-limiting examples include acarbose, chiorpromide, exenatide,gliclazide, glimepiride, glipizide, glyburide, insulin, metformin,miglitol, nateglinide, pioglitazone, pramlintide, repaglinide,rosiglitazone, and tolazamide.

Anti-psychotics include atypical anti-psychotics. Non-limiting examplesof anti-psychotics include clozapine, olanzapine, risperidone,aripiprazole, quetiapine, paliperidone, ziprasidone, and amisulpride.

Anti-convulsants include, but are not limited to, anti-epileptics andanti-seizure medications. Non-limiting examples of anti-convulsantsinclude topiramate, lamotrigine, pregabalin, tiagabine, and zonisamide.

Selective serotonin reuptake inhibitors include, but are not limited to,citalopram, escitalopram, femoxetine, fluoxetine, fluvoxamine,paroxetine, sertraline, and zimeldine.

Serotonin partial agonists include, but are not limited to, pindolol,gepirone, and flesinoxan.

Selective serotonin norepinephrine reuptake inhibitors include, but arenot limited to, duloxetine, venlafaxine, desvenlafaxine, milnacipran,and clovoxamine.

Norepephrine reuptake inhibitors include, but are not limited to,atomoxetine and reboxetine.

Serotonin-2 antagonist reuptake inhibitors include, but are not limitedto, trazodone.

Alpha-2 antagonist/serotonin 5HT2-3 receptor antagonists include, butare not limited to, mirtazapine.

Norepinephrine dopamine reuptake inhibitors include, but are not limitedto bupropion.

Tricyclic antidepressants include, but are not limited to, doxepin,amitriptyline, amoxapine, clomipramine, desipramine, doxepin,imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine.

Benzodiazepines include but are not limited to, alprazolam, clonazepam,diazepam, lorazepam, flurazepam, and bentazepam.

Anti-manics include, but are not limited to, carbamazepine, valproicacid and lithium.

Alpha-2 receptor agonists include but are not limited to guanfacine andclonidine.

Wakefulness promoting agents include but are not limited to modafiniland armodafinil.

Neurokinin-1 antagonists include but are not limited to casopitant.

Neurokinin-2 antagonists include but are not limited to saredutant.

Beta-3 adrenoreceptor agonists include but are not limited to amibegron.

CRF1 antagonists include but are not limited to pexacerfont.

An anti-obesity agent may include a cannaboid receptor ligand,antagonist, or inverse agonist; a fatty acid amide hydrolase inhibitor;a peptide YY; a serotonin 5-HT2c antagonist; an adipocyte11B-hydroxysteroid dehydrogenase type 1 antagonist; an amylaseinhibitor; an anti-angiogenesis inhibitor; an agouti-related peptideanalog, agonist, or antagonist; a carboxypeptidase inhibitor; a ciliaryneurotrophic factor; a cholecystokinin (CCK) analog, agonist orinhibitor; a corticotrophin relating hormone modulator, agonist, orantagonist; a CKGGRAKDC peptide; a dehydroepiandrosterone analog; afatty acid synthesis inhibitor; a fat-targeted peptide; a G-proteincoupled receptor (GCPR) modulator; a gastrointestinal lipase inhibitor;a ghrelin modulator, agonist or antagonist; a human growth hormone (HGH)analog or fragment; a growth harmone secrectogue receptor (GHS-R)modulator, agonist or antagonist; a lipase inhibitor; a leptin analog,transport and/or receptor promoter; a melanocortin (MC) receptor agonistor antagonist; an M4 receptor agonist or antagonist; a melaninconcentrating hormone (MCHR) agonist or antagonist; a melanocytestimulating hormone analog; a neuropeptide Y modulator, agonist orantagonist; a thyroid hormone;

a thyroid receptor agonist; an orexin modulator, agonist or antagonist;a peptide YY or related analog or stimulator; a phytostanol analog; apro-opiomelanocortin (POMC) stimulator; a somatostatin agonist; or aTNF-alpha antagonist.

An anti-diabetes agent may include a glucose-lowering (i.e.,hypoglycemic) agent; an alpha-glucosidase inhibitor; an amylin analog; abiguanide; an incretin mimetic or analog; a glucagon-like peptide-1(GLP-1) agonist or analog; a dipeptidyl peptidase (DPP) inhibitor; aDPP-IV inhibitor; a glucose-dependent insulinotropic peptide (GIP)agonist or analog; a gastric inhibitory peptide analog; a form ofinsulin (ie, injectable or inhaled); a fructose 1,6 biphosphatase(FBPase) inhibitor; a meglitinide; a peroxysome proliferators activatedreceptor (PPAR) modulator, agonist or antagonist; a PPAR-garnma agonistor antagonist; a protein-tyrosine phosphatase (PTP) 1B modulator,agonist or antagonist; a sodium-dependent glucose transporter (SGLT)inhibitor; a sulfonylurea; or a thiazolidinedione (ie, a “glitazone”).

The invention includes combination methods of treatment in which anamphetamine prodrug, such as lisdexamfetamine dimesylate, amethylphenidate prodrug, or a methylphenidate analog is providedtogether with a Norepinephrine/Dopamine Reuptake Inhibitor, a SerotoninReuptake Inhibitor, a Selective Serotonin Norepinephrine ReuptakeInhibitor, a Norepinephrine Reuptake Inhibitor, or an Anticonvulsant.For example the invention includes combination methods in which theamphetamine prodrug (e.g. lisdexamfetamine dimesylate) ormethylphenidate prodrug is provided in combination with one or more ofbupropion HCl, venlafaxine, paroxetine, mirtazapine, duloxetine,citalopram, escitalopram, fluoxetine, sertraline, atomoxetine,topiramate, zonisamide, lamotrigine, gabapentin, tiagabine, orpregabalin.

When treating binge eating the following active agents are particularlyuseful in combination with a methylphenidate prodrug or amphetamineprodrug: orlistat, bupropion, memantine, naltrexone, acamprosate,topiramate, zonisamide, sibutramine. Sibutramine may not be suitable forall patients because of its tendency to elevate pulse and bloodpressure. Zonisamide is effective for treatment of binge eating but isnot always well tolerated.

When treating depression the following active agents are particularlyuseful in combination with a methylphenidate prodrug or amphetamineprodrug: excitalopram, sertraline, fluoxetine, citalopram, bupropion,venlafaxine, and duloxetine,

Articles of Manufacture

The invention includes articles of manufacture, which comprise anamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogin a container and labeling stating that the amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog is effective fortreating certain central nervous system disorders; including treatingbinge eating disorders, obesity resulting from binge eating behavior,and depression. The labeling may also state that the amphetamineprodrug, methylphenidate prodrug, or methylphenidate analog is effectivefor treating certain co-morbidities in ADHD and ADD patients; forexample the invention includes methods of treating generalized anxietydisorder, obsessional and ruminative thought disorders, andobsessive/compulsive behavior in ADHD and ADD patients. The amphetamineprodrug, methylphenidate prodrug, or methylphenidate analog present inthis article of manufacture may be lisdexamfetamine dimesylate or someother amphetamine prodrug, methylphenidate prodrug, or methylphenidateanalog. The article of manufacture may comprise the amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog as the only activeagent or may include one or more additional active agents. Additionalactive agents may be combined in a single dosage form with theamphetamine prodrug, methylphenidate prodrug, or methylphenidate analogor may be packaged as separate dosage forms. The article of manufacturemay comprise packaging material and a dosage form of an amphetamineprodrug, methylphenidate prodrug, or methylphenidate analog containedwithin the packaging material, wherein the packaging material comprisesa label approved by a regulatory agency for the product. In certainembodiments the labeling is labeling approved by the United States FDA.

An example of an article of manufacture provided by the invention is apackaged pharmaceutical compositions comprising an amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog in a container andprinted labeling stating that the amphetamine prodrug, methylphenidateprodrug, or methylphenidate analog is useful for treating a binge eatingdisorder or associated symptoms, obesity resulting from binge eatingbehavior, or depression.

When an article of manufacture of this invention compriseslisdexamfetamine dimesylate, the labeling may advise administering 2.5mg to 250 mg, 2.5 mg to 12.5 mg, 2.5 to 15 mg, 10 to 100 mg per day, 20to 70 mg per day, or about 50 mg per day lisdexamfetamine dimesylate.The labeling may advise that lisdexamfetamine dimesylate is to beadministered once daily, but there may be clinical value in somepatients for up to two times per day.

Pharmaceutical Preparations

An amphetamine prodrug, methylphenidate prodrug, or methylphenidateanalog alone or in combination with one or more other active agent(s)can be administered as the neat chemical, but is preferably administeredas a pharmaceutical composition or formulation. Accordingly, theinvention provides pharmaceutical formulations comprising an amphetamineprodrug, methylphenidate prodrug, or methylphenidate analog alone or incombination with one or more other active agents together with one ormore pharmaceutically acceptable carriers. Pharmaceutical formulationscomprising lisdexamfetamine dimesylate have been previously described inU.S. Pat. No. 7,105,486, which is hereby incorporated by reference atcols. 13 to 17 for its teachings regarding amphetamine prodrugformulations including lisdexamfetamine dimesylate formulations.

An amphetamine prodrug, methylphenidate prodrug, or methylphenidateanalog alone or in combination with one or more other active agent(s)may be administered orally, topically, parenterally, by inhalation orspray, sublingually, transdermally, via buccal administration, or byother means, in dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, excipients, adjuvants,and vehicles. Oral dosages forms such as tablets, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs are preferred. Oraladministration is preferred for lisdexamfetamine dimesylateadministration. In some embodiments solid oral dosage forms arepreferred. Tablets, capsules, and inhalable (e.g. intranasal)preparations are preferred. Compositions intended for oral use may beprepared according to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents, such as sweetening agents, flavoring agents, coloringagents and preserving agents, in order to provide pharmaceuticallyelegant and palatable preparations.

Oral formulations contain between 0.1 and 99%, at least about 5% (weight%), 25% to about 50% or from 5% to 75% of an amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog alone or incombination with one or more other active agent(s) and usually at leastabout 5% (weight %) of a compound of the present invention.

In addition to the amphetamine prodrug, methylphenidate prodrug, ormethylphenidate analog alone or in combination with one or more otheractive agent(s), the compositions of the invention may contain apharmaceutically acceptable carrier, one or more compatible solid orliquid filler diluents or encapsulating substances, which are suitablefor administration to an animal. Carriers must be of sufficiently highpurity and sufficiently low toxicity to render them suitable foradministration to the animal being treated. The carrier can be inert orit can possess pharmaceutical benefits of its own. The amount of carrieremployed in conjunction with the compound is sufficient to provide apractical quantity of material for administration per unit dose of thecompound.

The pharmaceutical dosage forms may contain an amphetamine prodrug,methylphenidate prodrug, or methylphenidate analog as the only activeagent or may be combined with one or more additional active agents inthe same dosage form. Active agents suitable for combination with anamphetamine prodrug, methylphenidate prodrug or methylphenidate analogin a single dosage form have been listed above in the section titled“Combination Methods.” Particularly useful combination dosage formsinclude lisdexamfetamine in combination with at least one of thefollowing in a single dosage form: orlistat, memantine, naltrexone,acamprosate, topiramate, zonisamide, sibutramine, escitalopram,sertraline, fluoxetine, citalopram, bupropion, venlafaxine, andduloxetine.

Tablets and Capsules

Tablets typically comprise conventional pharmaceutically compatibleadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarrnelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, areuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability. Such compositions may also be coated by conventional methods,typically with pH or time-dependent coatings, such that the subjectcompound is released in the gastrointestinal tract in the vicinity ofthe desired topical application, or at various times to extend thedesired action. Such dosage forms typically include, but are not limitedto, one or more of cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose,Eudragit coatings, waxes and shellac.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

The invention includes amphetamine prodrug capsule formulations,particularly lisdexamfetamine dimesylate capsule formulations, 2.5 mg to250 mg, 2.5 mg to 12.5 mg, 2.5 to 15 mg, 10 to 100 mg per day, 20 to 70mg per day, or about 50 mg per day lisdexamfetamine dimesylate togetherwith one or more of microcrystalline cellulose, croscarmellose sodium,and magnesium stearate in a gelatin capsule. The invention also includesmethylphenidate tablets comprising 2.5 to 200 mg methylphenidate prodrugtogether with lactose, magnesium stearate, polyethylene glycol, starch,sucrose, talc, and gum tragacanth.

EXAMPLES

The following examples describe patients with binge eating disorder orassociated symptoms, a history of major depressive episodes, obsessivecompulsive behavior, generalized anxiety disorder, or attention deficithyperactivity disorder whose symptoms were poorly managed withpsychopharmacologic interventions. In the cases where binge eating anddepression were present, binge eating behavior significantly lessenedfollowing treatment with the amphetamine prodrug, lisdexamfetaminedimesylate; in one of these cases, it was thought that binge eatingsymptoms were due to antidepressant medication and the addition ofamphetamine prodrug lisdexamfetamine dimesylate decreased bingingbehavior. Additionally, patients treated with lisdexamfetaminedimesylate, either as a monotherapy or as an adjunct to existingtherapies, experienced remission of their depressive symptoms. Theexamples demonstrate the effectiveness of an amphetamine prodrug as amonotherapy or in combination with one or more other therapeutic agentsfor treating a range of psychological symptoms, including binge eatingand depression.

These case reports suggest the clinical efficacy of an amphetamineprodrug, methylphenidate prodrug, or methylphenidate analog in thetreatment of binge eating disorder or associated symptoms (in two casesthought to worsen from antidepressant agents), obesity resulting frombinge eating behavior, and depressive disorders, as either a monotherapyor as an adjunct to existing antidepressant pharmacotherapy. In additionthese cases also demonstrate that an amphetamine prodrug, amethylphenidate prodrug, or methylphenidate analog may offer significantclinical value in treatment of anxiety spectrum symptoms, includegeneralized anxiety disorder and obsessive compulsive behavior.

Example 1 Treatment of a Patient with Major Depressive Disorders andBinge Eating Disorder Using the Amphetamine Prodrug LisdexamfetamineDimesylate

Patient 1 is an adult, non-geriatric patient with a history of a majordepressive disorder, attention deficit hyperactivity disorder, and bingeeating disorder. Throughout Patient 1's entire adult life, there werereportedly periodic depressive episodes and symptoms. Patient 1 alsoindicated a history of binge eating disorder for approximately one year,characterized by eating unusually large amounts of junk food, oftenuntil feeling nauseated, and then feeling very guilty about the bingingbehavior. Such symptoms, though intermittently present for the past twodecades, had escalated to an average of nearly every other day for about12 months. During this time Patient 1 was being treated with PAXIL(paroxetine) and then ZOLOFT (sertraline) daily. Patient 1 participatedin group therapy to address mood and eating symptoms. However, grouptherapy did not prove helpful for managing the binging behavior; thenumber of episodes as well as the number of days binging continued onaverage every other day. Following group therapy, Patient 1 began toexperience a worsening depressed mood, poor concentration, and excessivefeelings of guilt, fatigue, and feelings of hopelessness. Priortreatments for this patient's major depressive disorder included PROZAC(fluoxetine), LEXAPRO (escitalopram), EFFEXOR (venlafaxine HCl), andWELLBUTRIN (bupropion Hal). Lisdexamfetamine dimesylate was added toPatient 1's 100 mg ZOLOFT (sertraline) therapy as this patient metcriteria of attention deficit hyperactivity disorder, with bothinattention and hyperactivity symptoms present since childhood, thoughthis diagnosis was not previously made for Patient 1. The dose oflisdexamfetamine dimesylate was titrated from 30 mg, to 50 mg, to 70 mg,in three successive weeks, respectively. Patient 1 reported significantimprovement in the prior symptoms of inattention, forgetfulness,procrastination and physical restlessness, among others, by the timePatient 1 was taking 70 mg of lisdexamfetamine dimesylate daily. Patient1 was maintained on that dose for an ensuing 8 weeks, along with 100 mgZOLOFT (sertraline), and reported having no more than 3 or 4 bingingepisodes in total and no more than 3 binging days for the 8 weeks thatPatient 1 was maintained at 70 mg lisdexamfetamine dimesylate daily.

Patient 1 experienced a reduction from approximately 12 or more bingeeating days per month, present for approximately one year, to no morethan 3 per month while taking the amphetamine prodrug lisdexamfetaminedimesylate, an approximately 75% reduction of binging eating days permonth. Patient 1 also noted full remission of depressive symptoms forthe 8 weeks of maintenance on 70 mg lisdexamfetamine dimesylate inaddition to 100 mg ZOLOFT (sertraline) noting significant improvement indepressed mood, concentration, feelings of guilt, fatigue and no longerexperienced any sense of hopelessness.

Example 2 Treatment of a Patient with Binge Eating Disorder and MajorDepressive Disorders Using Lisdexamfetamine Dimesylate

Patient 2 is a non-geriatric adult with a history of attention-deficithyperactivity disorder, polysubstance dependence, major depressivedisorder, generalized anxiety disorder, and binge eating disorder. Thepatient has been treated in the past with multiple medication trials,either alone or in combination, including: WELLBUTRIN (bupropion HCl),EFFEXOR (venlafaxine HCl), CELEXA (citalopram), LAMICTAL (lamotrigine),RISPERDAL (risperidone), NEURONTIN (gabapentin), KLONOPIN (clonazepam),STRATTERA (atomoxetine) CONCERTA (methylphenidate), RITALIN SR(methylphenidate), ADDERAL XR (dextroamphetamine+amphetamine), andPROVIGIL (modafinil). The patient also was previously treated withintensive psychotherapy and received various forms of substance abusecounseling in the past. Lisdexamfetamine dimesylate was initiated fortreatment of the patient's ADHD to address ‘wear off’ effects fromADDERALL XR in the later afternoons and early evenings. While thepatient experienced an underlying mild depressive disorder, such “wearoff” effects correlated with worsening of an already mildly depressedmood, further lowered overall energy level, even poorer concentrationand unsettled sleep. The patient also indicated hinging behavior in theevenings, typically characterized by rapidly devouring large amounts of“sweet” foods, while alone, and until feeling bloated. While the patientstruggled with binging behavior for the past two decades, the bingeeating symptoms intensified in the 6 months prior to startinglisdexamfetamine dimesylate treatment, occurring at least two days perweek, and causing an approximately 30 pound weight gain.Lisdexamfetamine dimesylate treatment was initiated, primarily fortreatment of Patient 2's attention deficit hyperactivity disorder toprovide greater coverage into the evening, with a dosing schedule of 30mg on day 1, 50 mg on day 2, and 70 mg on day 3; the patient had beentaking Adderall XR 30 mg per day, which was discontinued on day 1 ofstarting lisdexamfetamine dimesylate. The patient was maintained onlisdexamfetamine dimesylate for about 10 weeks.

Patient 2 noted an overall improvement in depressive symptoms, includingdepressed mood, general interest level in activities especially in theevenings, sleep quality, and physical fatigue. Patient 2 also noted amarked reduction in binging episodes, both in terms of the total numberand total days of binges; such binging episodes occurred only once inthe first 2 weeks of treatment and stopped entirely in the subsequent 8weeks of treatment with lisdexamfetamine dimesylate. The patient,considered obese prior to starting lisdexamfetamine dimesylate, lostapproximately 7% of total body weight while taking the amphetamineprodrug. Interestingly, triglyceride levels present prior to takinglisdexamfetamine dimesylate were 271 mg/dL and reduced to 160 mg/dL bythe end of 5 weeks of treatment with lisdexamfetamine dimesylate.

This case report exemplifies the utility of an amphetamine prodrug as amonotherapy for depression treatment, as demonstrated in this patientwith an underlying depressive disorder, untreated with antidepressantmedication at the time of initiating lisdexamfetamine dimesylate, whoshowed significant improvement across all the patient's depressivesymptoms. The effectiveness of lisdexamfetamine dimesylate monotherapyin treating the patient's treatment resistant depression is particularlyremarkable in view of Patient 2's number of failed treatments ofrecurrent major depressive disorder. Prior treatments failed due to poortreatment response and medication side effect intolerability. It shouldbe noted that Patient 2's ADHD symptoms were not at issue at the timelisdexamfetamine dimesylate monotherapy was begun. The patient's ADHDsymptoms were adequately addressed with ADDERALL XR treatment.Lisdexamfetamine dimesylate monotherapy was started to address theadverse effects Patient 2 had experienced from ADDERALL XR treatment.Lisdexamfetamine dimesylate proved as effective as ADDERALL XR inaddressing the patient's ADHD symptoms, demonstrated sustained and fullday antidepressant efficacy, and functioned as an antidepressant inaddition to alleviating ADHD symptoms.

Example 3 Treatment of a Patient with ADHD, Generalized AnxietyDisorder, and Obsessive-Compulsive Behavior Using LisdexamfetamineDimesylate

The patient is a non-geriatric adult diagnosed with a history of ADHD,inattentive type, and comorbid Generalized Anxiety Disorder, though hadno prior treatment. Presenting ADHD symptoms included difficultysustaining attention and attending to details, difficulty organizingtasks with tendencies toward avoidance, distractibility, and problemsfinishing tasks that have been initiated. Symptoms of GeneralizedAnxiety Disorder included frequent and intense ruminative worrying,feeling overly fatigued, muscle tension and intermittent problems withsleep. History suggests that a perseverative pattern of thinking andcompulsive worrying may have evolved from deficits in attention andinformation processing. The patient was started on VYVANSE 30 mg in themorning, along with TRAZODONE 50 mg at bedtime. VYVANSE was maintainedat 30 mg once daily in the morning for one week, followed by one week at50 mg per day, and then 70 mg per day, taken in the morning. The patientexperienced a positive effect across all ADHD and Generalized AnxietyDisorder symptoms within the first week, with more dramatic improvementas the dose of VYVANSE was increased. The patient maintained treatmenton VYVANSE at 70 mg per day for 10 weeks; TRAZODONE 50 mg at bedtime wasdiscontinued after 4 weeks as sleep patterns had sufficientlynormalized. While maintained on VYVANSE at 70 mg per day, the patientnoted significantly enhanced ability to sustain attention and attend todetails, organize and finish projects, and process information ascompared to previous baseline function, with clear and evidentimprovements in work function. The patient found, surprisingly, a highlysignificant improvement on compulsive ruminating and worrying. Thepatient previously felt little or no control around such worrying,ruminative behavior and speculated that it caused significant mental andeven physical fatigue. After 10 weeks of treatment with VYVANSE at 70 mgper day, the patient reported being only mildly affected by inattentionsymptoms and preoccupied primarily with ‘realistic kinds of worries’that were generally well-managed.

This case demonstrates the use of an amphetamine prodruglisdexamfetamine dimesylate as monotherapy for comorbid ADHD and anxietyspectrum symptoms, most notably generalized anxiety (in this caseGeneralized Anxiety Disorder) that took on a perseverative and‘compulsive worrying’ quality along with physical symptoms of fatigueand muscle tension. Stimulant medications have traditionally beenassociated with causing or worsening anxiety symptoms (for instance,being ‘anxiogenic’). It is thus surprising that an amphetamine prodrugproved useful for treating the Generalized Anxiety Disorder symptoms forthe duration of the day, with no problematic ‘wear off’.

Example 4 Treatment of Patient with Comorbid Depressive Disorders andBinge Eating Behavior with Lisdexamfetamine Dimesylate

The patient is a non-geriatric adult with a history of intermittentmajor depressive disorder, dysthymic disorder, and binge eatingbehavior. The patient also endorsed symptoms of ADHD, inattentive type,primarily around problems with organizing tasks, procrastination of workactivities, and problems completing projects, though such ‘inattention’symptoms were considered as clinically less detrimental than feelingchronically depressed, lacking motivation or interest in work or socialactivities, feeling fatigued and sometimes guilty, and having gainedweight over several years due to ‘emotional eating’ behavior. Thepatient had received therapy in the past to address depressive episodesand associated life stressors, with modest benefit. The patient alsodescribed a history of ‘emotional eating’ that could occur at any timeof day though more often in the late afternoons or early evenings. Such‘emotional eating’ was often triggered by stressful situations orevents, accompanied by an urge to eat, and would typically lead toexcess consumption of carbohydrate-based foods. In recent years, thepatient reported having gained over 10% body weight and noted a generaltrend toward increasing emotional eating and binging behavior. Moresevere binges occurred at least several times per month over a stretchof several years, though were much less common than ‘emotional eating’that was milder in nature and occurred nearly daily. Medicationtreatment was initiated with VYVANSE at 30 mg per day for two weeks andthe dose was increased to 50 mg per day, without any adverse effects.The patient was maintained on VYVANSE for 10 weeks at 50 mg per day. Thepatient reported a rather abrupt and sustained cessation of emotionaleating behavior in the afternoon while taking 50 mg VYVANSE daily.Symptoms of emotional eating were improved in the evenings as well, withless than one per week on average as compared to most eveningspreviously. There were no reported major binges reported at any pointwhile taking VYVANSE and the patient lost approximately 6-7 pounds over2′2 months of treatment. The patient also noted significant ameliorationof depressive symptoms, of feeling chronically low, and feltsufficiently motivated and invested in work and social activities in away that was not present for some time. The organization and executionof work-related tasks improved during the course of treatment as well.

The case report demonstrates successful treatment of a comorbiddepressive disorder (both major depressive disorder and dysthymicdisorder) and binge-eating behavior with the amphetamine prodruglisdexamfetamine dimesylate. The patient also began a trend of weightloss on account of decreased emotional eating and binging. The patient'sADHD was also clinically relevant, which is the primary reason VYVANSEwas chosen as the initial medication treatment, though it was not thereason for which evaluation and treatment was sought and of secondaryimportance with regard to symptoms causing the patient difficulty andconcern. Clinical improvement on depressive symptoms was present, mostnotably improved interest in daily activities and overall mood.Binge-eating behavior, largely taking the form of ‘self-soothing’ eatingactivity with potentially serious risks in this patient insofar as itwas causing steady increased weight gain to the point of obesity),responded remarkably well to treatment with VYVANSE. The patient'ssymptoms of ADHD, inattentive type, also demonstrated improvement andenhanced an overall sense of improved well being, effectiveness, andconfidence.

Example 5 Treatment of Binge Eating Disorder, Medication-InducedCognitive Problems, and Fatigue with Lisdexamfetamine Dimesylate

The patient is a non-geriatric adult with a history of recurrent majordepressive disorder with comorbid anxiety symptoms and severe bingeeating disorder. The patient previously has been treated with therapyand has had multiple prior medication trials, either discontinued due tolack of efficacy or side effects, including ZOLOFT (sertraline), CELEXA(citalopram), PROZAC (fluoxetine), LEXAPRO (escitalopram), WELLBUTRIN SR(bupropion HCl), NORTRIPTYLINE, ATIVAN (lorazepam), ABILIFY(aripiprazole), RISPERDAL (risperidone), SEROQUEL (quetiapine), LYRICA(pregabalin), and RITALIN (methylphenidate). Selective serotoninreuptake inhibitors exacerbated binge eating symptoms and causedproblematic weight gain. For treatment of depression with comorbidanxiety, binge-eating, and weight-gain related to binge eating symptoms,the patient was maintained on a medication regimen that included TOPAMAX(topiramate) 175 mg in the morning and 200 mg at night, LAMICTAL(lamotrigine) 200 mg in the morning, CYTOMEL (liothyronine) 25 mcg perday, KLONOPIN (clonazepam) 0.25 mg at bed time, and NEURONTIN(gabapentin) 600 mg at bedtime. However, symptoms of depressed mood,hopelessness, amotivation, problems with concentration (possiblyworsened with the use of TOPAMAX though prior attempts to decrease thedose exacerbated binge-eating symptoms), significant fatigue, andtendency toward emotional eating and hinging significantly increasedfrom baseline. Given prior poor response to a number of differentclasses of medication trials, off-label use of VYVANSE was initiated at30 mg each morning to target a constellation of symptoms, includingsymptoms of major depression, binge-eating disorder, fatigue, andconcentration problems. VYVANSE was maintained at 30 mg each morning forweeks before being discontinued due to adverse effects. These sideeffects were excessive appetite suppression and visual blurring.However, during the time of treatment, the patient indicated a notablyreduced urge to binge, fewer absolute binges per week, fewerbinge-eating days per week, and improvement in both fatigue andconcentration throughout the day. However, there appeared to be nobenefit on the patient's depressed mood, amotivation, and feelings ofhopelessness.

This case exemplifies the clinical benefit of lisdexamfetaminedimesylate on binge-eating symptoms and potentially on weight-gainrelated to binging (body weight was not obtained), though longer-termtreatment was cut short by adverse effects at the 30 mg, dosage form.Given the number of failed prior trials, off-label use of VYVANSE wasclinically indicated, especially given the severity of binge eatingbehavior. Though TOPAMAX helped reduce binge eating behavior, it wasclinically insufficient to fully address binge eating behavior, as itwas poorly tolerated at higher doses due to cognitive side effects, andmay have had a contributory role in cognitive slowing and fatigue at themaintenance dose.

Example 6 Treatment of a Patient with Comorbid Generalized AnxietyDisorder, Major Depression, and ADHD with Lisdexamfetamine Dimesylate

Patient 6 is a non-geriatric adult with a history of Generalized AnxietyDisorder and Major Depressive Disorder. The patient was maintained onPAXIL (paroxetine) 30 mg per day following a significant comorbid majordepressive episode associated with anxiety symptoms, and a historyconsistent with Generalized Anxiety Disorder. Treatment with PAXIL hadrapidly stabilized both depressive and anxiety symptoms and forapproximately 2 years the patient was maintained at 30 mg per day withno change in dose. Over this time, the patient had gained approximately10% of their body weight. It was periodically addressed that the patientmay have experienced previous academic difficulties due to ADHD,inattentive type, though during the course of treatment with PAXIL, thepatient was generally able to adapt to work pressures and developedcompensatory strategies to deal with organizational difficulties,auditory inattention and forgetfulness, and feeling poorly engaged.However, after beginning a new job with more challengingresponsibilities, the patient was unable to compensate for such deficitsand a pattern of obsessive ruminations emerged, often involving work. Inaddition to perseverative and obsessive thinking, the patientexperienced heightened anxiety and mild depressive symptoms, includingfatigue, low mood, and amotivation, especially while at work. Afterdiscussing medication options and side effect concerns, VYVANSE wasinitiated to address underlying ADHD symptoms, which were felt to drivethe patient's perseverative thinking, anxious ruminations, and low mood.VYVANSE was initiated at 30 mg per day for one week, and then titratedto 50 mg per day, without adverse effect. PAXIL was maintained at 30 mgper day. Over the course of the ensuing 9 weeks, the patient reportedimprovement across ADHD, Generalized Anxiety Disorder, and MajorDepressive Disorder symptoms. Work function began to feel ‘easier’, withbetter ability to attend to tasks and more efficient performance,improved attention to detail, and feeling internally less restless. Thepatient reported a substantial reduction in worrying, an approximate4-5% weight loss over 2 months of treatment, and improved mood,motivation and energy.

The case report exemplifies the use of the amphetamine prodruglisdexamfetamine dimesylate to address multiple clinical issues, themost unexpected one being the alleviation in generalized anxietysymptoms, perseverative thinking, and obsessive ruminations. Thepatient's initial presenting symptoms in past treatment have been withinthe class of Anxiety Disorders, mainly of Generalized Anxiety Disorderbut also possibly Obsessive-Compulsive Disorder, as well as within theclass of Depressive Disorders, mainly Major Depressive Disorder. Whilethe patient may have exhibited ADHD symptoms in the past, they wereconsidered clinically of a secondary nature, such that pharmacologictreatment had been initiated with the selective serotonin reuptakeinhibitor (SSRI) PAXIL (paroxetine) to target both depressive andanxiety spectrum symptoms. The use of the amphetamine prodrug VYVANSEwas able to accomplish a number of clinically very important objectives,with full-day duration effects, including augmentation of themood-enhancing effect of the antidepressant PAXIL, alleviation ofanxiety spectrum symptoms (including worrying and obsessive/compulsivemental behavior), and reduction of ADHD symptoms.

1-15. (canceled)
 16. A method of using lisdexamfetamine dimesylatecomprising informing a user that the lisdexamfetamine dimesylate may beused to treat Binge Eating Disorder as defined in the DSM-IV-TR. 17-18.(canceled)
 19. The method of claim 16, additionally comprising providinglisdexamfetamine dimesylate in a container and the informing is byreference to a package insert associated with the container.
 20. Themethod of claim 16, wherein the informing is by reference to informationmaterial; by reference to a package active agent insert, a flyer or anadvertisement; by presentation of information at a seminar, conference,or other educational presentation; or by a conversation between apharmaceutical sales representative and a medical care worker. 21-25.(canceled)
 26. A method of using lisdexamfetamine dimesylate comprising(i) conducting a clinical trial of the efficacy of the lisdexamfetaminedimesylate for treating Binge Eating Disorder as defined in DSM-IV-TRand (ii) informing a purchaser of the lisdexamfetamine dimesylate thatthe lisdexamfetamine dimesylate is efficacious for treating Binge EatingDisorder. 27-28. (canceled)
 29. The method of claim 26, wherein theclinical trial generates data that is submitted to the FDA.